Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV

Abstract

Roughly one-third of individuals living with the human immunodeficiency virus (HIV) are coinfected with the hepatitis C virus (HCV) due to shared routes of transmission. HIV accelerates the progression of HCV disease; thus, coinfected individuals are at high priority for HCV treatment. Several new HCV therapies, called direct-acting antiviral agents (DAAs), are available that achieve cure rates of >90% in many patient populations including individuals with HIV. The primary consideration in treating HCV in HIVinfected persons is the potential for drug interactions. We describe the clinical pharmacology and drug interaction potential of the DAAs, review the interaction data with DAAs and antiretroviral agents, and identify the knowledge gaps in the pharmacologic aspects of treating HCV in individuals with HIV coinfection. This review will focus on DAAs that have received regulatory approval in the United States and Europe and agents in late stages of clinical development.Keywords. hepatitis C virus; human immunodeficiency virus; coinfection; drug interactions; direct-acting antivirals.Roughly one-third of individuals living with the human immunodeficiency virus (HIV) are coinfected with the hepatitis C virus (HCV) due to shared routes of transmission [1,2]. HIV accelerates the progression of HCV disease. Individuals with HIV coinfection have higher HCV RNA, a more rapid progression of fibrosis, and an increased frequency of liver decompensation and death [3][4][5][6]. Due to the increased risks associated with HIV coinfection, treatment guidelines consider this patient population a "high priority" for HCV treatment [7,8].There have been significant advances in the treatment of HCV in recent years. Pegylated interferon alfa (PEG) and ribavirin (RBV) were the standard of care for this disease for decades, but several agents that directly target specific steps in the HCV lifecycle (Figure 1) have recently received regulatory approval [9]. The approved direct-acting antiviral agents (DAAs) inhibit 3 specific steps in the HCV lifecycle including the NS3/4A protease enzyme, NS5A protein, and the NS5B polymerase. Inhibition of the NS3 protease prevents the cleavage of the replication complex responsible for formation of viral RNA. The NS5B enzyme is essential for HCV replication as it catalyzes the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA. There are 2 types of NS5B RNA-dependent RNA polymerase inhibitors: nucleotide and nonnucleoside inhibitors. The nucleotide inhibitors are active site inhibitors, whereas the nonnucleoside inhibitors are allosteric inhibitors. Another target, NS5A, encodes a protein that appears to be essential to the replication machinery of HCV and critical in the assembly of new infectious viral particles. However, the specific functions of this protein have not been established.Relative to PEG plus RBV, DAAs are well tolerated, administered for shorter treatment durations (eg, 8-24 weeks), and ultimately achieve high rates of cure (>90%), otherwise known...

Highly Successful Hepatitis C Virus (HCV) Treatment Outcomes in Human Immunodeficiency Virus/HCV-Coinfected Patients at a Large, Urban, Ryan White Clinic

“…Patients infected with HIV are often on a number of medications in addition to ART that may interact with DAAs [23]. In this study, several patients required medication modifications due to drug interactions with the selected HCV treatment regimen.…”

Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis

“…Paritaprevir AUC values decreased by 29% in patients with mild hepatic failure and increased by 62 and 945%, respectively, in subjects with moderate and severe hepatic impairment compared to subjects with normal hepatic function (14, 15). Grazoprevir exposures were increased 62% in patients with mild (Child-Pugh class A) and 388% in patients with moderate (Child-Pugh class B) hepatic impairment relative to those with no hepatic impairment (16). The difference in our study is that all components of the combination, including ritonavir, were given in a single therapeutic dose.…”

Diagnosis and Management of Hepatitis C Infection in Primary Care Settings

“…11 The major issue in the treatment of such patients, however, is the risk of drug-drug interactions. 39 Adjustments in HIV medications are often needed, so close collaboration with infectious disease providers is recommended.…”